Acyl guanidine compounds and use thereof

ABSTRACT

Acyl guanidine compounds of the following Formula  
                 
 
     wherein R 1 , R 2 , R 3 , R 4  and L are described herein, and pharmaceutical compositions thereof, are useful in treating leukocyte activation-associated disorders.

[0001] This application claims priority from U.S. provisionalapplication serial No. 60/424,237 filed Nov. 6, 2002, the entirely ofwhich is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to acyl guanidine compounds,pharmaceutical compositions containing these compounds, and the use ofthese compounds in the treatment of leukocyte activation-associateddisorders.

BACKGROUND OF THE INVENTION

[0003] The immune system plays an important role in host defense. In thetreatment of leukocyte activation-associated disorders is oftendesirable to attenuate the immune response. Such disorders include theimmune response incurred by transplantation or diseases improved bydecreased T-cell activation and proliferation. It is accepted thatagents that inhibit T-cell proliferation may be useful in the treatmentof the aforementioned disorders.

[0004] A number of agents demonstrate clinical or therapeutic utility byattenuating or modulating the immune system. Such agents includeCyclosporin A (“CsA”), azathioprine, tacrolimus, sirolimus andmycophenolate mofetil. However, these agents often demonstrate arelatively high incidence (25 to >50%) of multiple unique liabilitiesduring clinical or therapeutic use. For example, CsA therapy isassociated with nephrotoxicity, azathioprine therapy is associated withleukopenia, and tacrolimus therapy is associated with undesirableeffects on the central nervous system. Also, sirolimus therapy isassociated with hypertension, hyperlipidemia and hypercholesterolemia,and mycophenolate mofetil therapy is associated with diarrhea.

[0005] The overproduction of cytokines, such as TNF-α, is alsoimplicated in a wide variety of leukocyte activation-associateddisorders, including rheumatoid arthritis (RA), psoriasis, multiplesclerosis, inflammatory bowel disease, endotoxin shock, osteoporosis,Alzheimer's disease and congestive heart failure, among others. Seee.g., Henry et al., Drugs Fut., 24:1345-1354 (1999); Salituro et al.,Curr. Med. Chem., 6:807-823 (1999). There is convincing evidence inhuman patients that cytokine protein antagonists can provide treatmentfor these disorders. See e.g., Rankin et al., Br. J. Rheumatol.,34:334-342 (1995) (monoclonal antibody to TNF-α—Enbrel®); and Morelandet al., Ann. Intern. Med., 130:478-486 (1999) (soluble TNF-α receptor-Fcfusion protein—etanercept). Accordingly, it is accepted that agentsdemonstrating TNF-α inhibitory activity are useful for the treatment ofleukocyte activation-associated disorders.

[0006] As none of the current treatments provide complete relief ofsymptoms and are often associated with various liabilities, new agentsand improved methods for treating leukocyte activation-associateddisorders are needed.

SUMMARY OF THE INVENTION

[0007] The present invention provides novel fused heterocyclic compoundsof the following Formula (I), their enantiomers, diastereomers, andpharmaceutically acceptable salts, prodrugs and solvates thereof, foruse in treating leukocyte activation-associated disorders,

[0008] in which:

[0009] R¹ and R⁴ are independently hydrogen or alkyl optionallyindependently substituted where valence allows with one to three groups,T¹, T² and/or T³;

[0010] R² is

[0011] W is O or S:

[0012] Y¹ is —NHT¹² or OT⁷;

[0013] Y² and Y³ are independently hydrogen, halo, OT⁷, alkyl orhaloalkyl;

[0014] Y⁴ is optionally substituted heteroaryl, cyano, C(O)_(t)T⁷ orS(O)_(t)NT¹¹T¹²; and

[0015] Y⁵ is alkyl, haloalkyl, NHT¹² or OT⁷;

[0016] R³ is O, S or N;

[0017] L is aryl, cycloalkyl, heterocyclo or heteroaryl, any of which isindependently substituted where valence allows by one to three groups,R⁵, R⁶ and/or R⁷;

[0018] R⁵, R⁶ and R⁷ are independently

[0019] (1) H, alkyl, halo, cyano, nitro, OH, OR¹⁰, oxo, SH, aryl,cycloalkyl, heterocyclo or heteroaryl, any of which is optionallyindependently substituted where valence allows with one to three groupsT⁴, T⁵ and/or T⁶, provided that when L is aryl or heteroaryl none of R⁵,R⁶ and R⁷ are oxo; or

[0020] (2) N(R⁸)(R⁹), —C(O)N(R⁸)(R⁹), S(O)_(t) N(R⁸)(R⁹), —S(O)_(t)R¹⁰or C(O)_(t)R¹⁰;

[0021] R⁸ and R⁹ are

[0022] (1) independently H, alkyl, alkenyl, aryl, (aryl)alkyl,heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl,heterocyclo or (heterocyclo)alkyl, any of which is optionallyindependently substituted where valance allows with one to three groupsindependently selected from T⁴, T⁵ and/or T⁶; or

[0023] (2) R⁸ and R⁹ may be taken together with the nitrogen atom towhich they are attached to form a heterocyclo or heteroaryl ring, eitherof which is optionally independently substituted where valance allowswith one to three groups independently selected from T⁴, T⁵ and/or T⁶;

[0024] R¹⁰ is H, alkyl or substituted alkyl;

[0025] T¹-T³ are each independently halo, cyano, nitro, OH, oxo, —OT⁷,—SH, —ST⁷, amino, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl,alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,(cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl,heteroaryl or (heteroaryl)alkyl;

[0026] T⁴-T⁶ are each independently

[0027] (1) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,(aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl or(heteroaryl)alkyl, any of which may be optionally independentlysubstituted where valence allows by one or more groups selected fromalkyl, (hydroxy)alkyl, halo, cyano, nitro, OH, oxo, (alkoxy)alkyl,alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,(cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyo)alkyl,heteroaryl, (heteroaryl)alkyl, —OT⁷, —SH, —ST⁷, —C(O)_(t)H, —C(O)_(t)T⁷,—O—C(O)T⁷, —SO₃H, —S(O)_(t)T⁷, S(O)_(t)N(T⁸)T⁷, -T⁹-NT¹¹T¹²,-T⁹-N(T⁸)-T¹⁰-T¹¹T¹², -T⁹-N(T¹³)-T¹²-T⁷ and -T⁹-N(T¹³)-T¹⁰-H; or

[0028] (2) halo, cyano, nitro, OH, oxo, —OT⁷, —SH, —ST⁷, —OT⁷, —SH,—ST⁷, —C(O)_(t)H, —C(O)_(t)T⁷, —O—C(O)T⁷, —SO₃H, —S(O)_(t)T⁷,S(O)_(t)N(T⁸)T⁷, -T⁹-NT¹¹T¹², -T⁹-N(T⁸)-T¹⁰-NT¹¹T¹², -T⁹-N(T¹³)-T¹²-T⁷or -T⁹-N(T¹³)-T¹⁰-H;

[0029] t is 1 or 2;

[0030] T⁷ is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or(heteroaryl)alkyl;

[0031] T⁹ and T¹⁰ are each independently a single bond,-T⁴-S(O)_(t)-T¹⁵-, -T¹⁴-C(O)-T¹⁵-, -T¹⁴-C(S)-T¹⁸-, -T¹⁷-O-T¹⁸-,-T¹⁷-S-T¹⁸-, -T¹⁷-O—C(O)-T¹⁸-, -T¹⁷-C(O)_(t)T¹⁸-, -T¹⁷-C(═NT¹⁶)-T¹⁵- or-T¹⁴-C(O)—C(O)-T¹⁵-;

[0032] T⁸, T¹¹, T¹², T¹³ and T¹⁶ are

[0033] (1) independently hydrogen, alkyl, (hydroxy)alkyl, (alkoxy)alkyl,alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,(cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl,heteroaryl or (heteroaryl)alkyl, any of which may be optionallyindependently substituted where valence permits by one or more groupsselected from alkyl, (hydroxy)alkyl, halo, cyano, nitro, OH, oxo,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyo)alkyl, heteroaryl, (heteroaryl)alkyl, —SH, —ST¹⁹, —C(O)_(t)H,—C(O)_(t)T¹⁹, —O—C(O)T¹⁹ and —S(O)_(t)T¹⁹; or

[0034] (2) independently halo, cyano, nitro, OH, oxo, SH, —ST¹⁹,—C(O)_(t)H, —C(O)_(t)T¹⁹, —O—C(O)T¹⁹ or —S(O)_(t)T¹⁹; or

[0035] (3) T¹¹ and T¹² may together be alkylene or alkenylene,completing a 3- to 8-membered saturated or unsaturated ring togetherwith the atoms to which they are attached, which ring is substitutedwith one or more groups listed in the description of T¹⁷; or

[0036] (4) T¹¹ or T¹², together with T⁸, may be alkylene or alkenylenecompleting a 3- to 8-membered saturated or unsaturated ring togetherwith the nitrogen atoms to which they are attached, which ring issubstituted with one or more groups independently selected from T¹⁷; or

[0037] (5) T¹¹ and T¹² or T⁸ and T¹³ together with the nitrogen atom towhich they are attached may combine to form a group —N═CT¹⁷T¹⁸;

[0038] T¹⁴ and T¹⁵ are each independently a single bond, alkylene,alkenylene or alkynylene;

[0039] T¹⁷ and T¹⁸ are each independently hydrogen, alkyl,(hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocylco)alkyl, heteroaryl or (heteroaryl)alkyl, any ofwhich may be optionally independently substituted where valence permitsby one or more groups selected from alkyl, (hydroxy)alkyl, halo, cyano,nitro, OH, oxo, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyo)alkyl, heteroaryl, (heteroaryl)alkyl, —SH,—ST¹⁹, —C(O)_(t)H, —C(O)_(t)T¹⁹, —O—C(O)T¹⁹ and —S(O)_(t)T¹⁹; and

[0040] T¹⁹ is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or(heteroaryl)alkyl.

DETAILED DESCRIPTION

[0041] The following are definitions of the terms as used throughoutthis specification and claims. The initial definition provided for agroup or term herein applies to that group or term throughout thepresent specification, individually or as part of another group, unlessotherwise indicated.

[0042] The terms “alk” or “alkyl” refer to straight or branched chainhydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbonatoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,t-butyl, pentyl, hexyl, heptyl, octyl, etc. Lower alkyl groups, that is,alkyl groups of 1 to 6 carbon atoms, are generally most preferred.

[0043] The term “substituted alkyl” refers to alkyl groups substitutedwith one or more groups listed in the definition of T⁴-T⁶, preferablyselected from halo (e.g. halo substituted alkyl [or “haloalkyl”] may beCHF₂, CH₂F, or CF₃), cyano, O—R₁₁, S—R₁₁, NR₁₂R₁₃, nitro, cycloalkyl,substituted cycloalkyl, oxo, aryl, substituted aryl, heterocyclo,heteroaryl, CO₂R₁₁, S(O)R₁₁, SO₂R₁₁, SO₃R₁₁, SO₂NR₁₂R₁₃, C(O)NR₁₂R₁₃,C(O)alkyl and C(O)H.

[0044] The term “alkylene” refers to a straight chain bridge of 1 to 4carbon atoms connected by single bonds (e.g., —(CH₂)_(x)— wherein x is 1to 5), which may be substituted with one or more groups listed in thedefinition of T⁴-T⁶.

[0045] The term “alkenyl” refers to straight or branched chainhydrocarbon groups having 2 to 12 carbon atoms, preferably 2 to 4 carbonatoms, and at least one double carbon to carbon bond (either cis ortrans), such as ethenyl.

[0046] The term “substituted alkenyl” refers to an alkenyl group asdefined above substituted with one or more groups listed in thedefinition of T⁴-T⁶, preferably selected from halo, cyano, O—R₁₁, S—R₁₁,NR₁₂R₁₃, nitro, cycloalkyl, substituted cycloalkyl, oxo, aryl,substituted aryl, heterocyclo, heteroaryl, CO₂R₁₁, S(O)R₁₁, SO₂R₁₁,SO₃R₁₁, SO₂NR₁₂R₁₃, C(O)NR₁₂R₁₃, C(O)alkyl and C(O)H.

[0047] The term “alkynyl” refers to straight or branched chainhydrocarbon group having 2 to 12 carbon atoms and one, two or threetriple bonds, preferably 2 to 6 carbon atoms and one triple bond.

[0048] The term “substituted alkynyl” refers to an alkynyl group asdefined above substituted with one or more groups listed in thedefinition of T⁴-T⁶, preferably selected from halo, cyano, O—R₁₁, S—R₁₁,NR₁₂R₁₃, nitro, cycloalkyl, substituted cycloalkyl, oxo, aryl,substituted aryl, heterocyclo, heteroaryl, CO₂R₁₁, S(O)R₁₁, SO₂R₁₁,SO₃R₁₁, SO₂NR₁₂R₁₃, C(O)NR₁₂R₁₃, C(O)_(t)alkyl and C(O)H.

[0049] The term “amino” refers to a nitrogen atom substituted with threegroups selected from hydrogen and alkyl (preferably lower alkyl) groups.Each alkyl group may be optionally substituted with one or more groupslisted in the definition of T⁴-T⁶.

[0050] The term “carbonyl” refers to C═O, which may also be designatedas C(O).

[0051] The group —C(O)_(t)X refers to C═O where t is 1 and the structure

[0052] where t is 2.

[0053] The term “halo” or halogen refers to chloro, bromo, fluoro, andiodo.

[0054] The term “cycloalkyl” refers to saturated and partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl andtricyclicalkyl, containing a total of 3 to 20 carbons forming the rings,preferably 3 to 7 carbons, forming the ring and which may be fused to 1or 2 aromatic or heterocyclo rings, which include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclodecyl, cyclododecyl, cyclohexenyl,

[0055] and the like.

[0056] The term “substituted cycloalkyl” refers to such cycloalkyl groupas defined above substituted with one or more groups listed in thedefinition of T⁴-T⁶ preferably selected from halogen, nitro, alkyl,substituted alkyl, alkenyl, cyano, cycloalkyl, substituted cycloalkyl,aryl, substituted aryl, heterocyclo, heteroaryl, oxo, OR₁₁, CO₂R₁₁,C(O)NR₁₂R₁₃, OC(O)R₁₁, OC(O)OR₁₁, OC(O)NR₁₂R₁₃, OCH₂CO₂R₁₁, C(O)R₁₁,NR₁₂R₁₃, NR₁₄C(O)R₁₁, NR₁₄C(O)OR₁₁, NR₁₄C(O)C(O)OR₁₁,NR₁₄C(O)C(O)NR₁₂R₁₃, NR₁₄C(O)C(O)alkyl, NR₁₄C(NCN)OR₁₁, NR₁₄C(O)NR₁₂R₁₃,NR₁₄C(NCN)NR₁₂R₁₃, NR₁₄C(NR₁₅)NR₁₂R₁₃, NR₁₄SO₂NR₁₂R₁₃, NR₁₄SO₂R₁₁, SR₁₁,S(O)R₁₁, SO₂R₁₁, SO₃R₁₁, SO₂NR₁₂R₁₃, NHOR₁₁, NR₁₄NR₁₂R₁₃, N(COR₁₁)OR₁₄,N(CO₂R₁₁)OR₁₄, C(O)NR₁₄(CR₁₆R₁₁)_(r)R₁₁,CO(CR₁₆R₁₇)_(p)O(CR₁₂R₁₃)_(q)CO₂R₁₁, CO(CR₁₆R₁₇)_(r)OR₁₁,CO(CR₁₆R₁₇)_(p)O(CR₁₈R₁₃)_(q)R₁₁, CO(CR₁₆R₁₇)NR₁₂R₁₃,OC(O)O(CR₁₆R₁₇)_(m)NR₁₂R₁₃, OC(O)N(CR₁₆R₁₇)_(r)R₁₁,O(CR₁₆R₁₇)_(m)NR₁₂R₁₃, NR₁₄C(O)(CR₁₆R₁₇)_(r)R₁₁,NR₁₄C(O)(CR₁₆R₁₇)_(r)OR₁₁, NR₁₄C(═NC)(CR₁₆R₁₇)_(r)R₁₁,NR₁₄CO(CR₁₆R₁₇)_(r)NR₁₂R₁₃, NR₁₄(CR₁₆R₁₇)_(m)OR₁₁,NR₁₄(CR₁₆R₁₇)_(r)CO₂R₁₁, NR₁₄(CR₁₆R₁₇)_(m)NR₁₂R₁₃,NR₁₄(CR₁₆R₁₇)_(n)SO₂(CR₁₈R₁₃)_(q)R₁₁,CONR₁₄(CR₁₆R₁₇)_(n)SO₂(CR₁₈R₁₃)_(q)R₁₁,SO₂NR₁₄(CR₁₆R₁₇)_(n)CO(CR₁₈R₁₉)_(q)R₁₁ and SO₂NR₁₄(CR₁₆R₁₇)_(m)OR₁₁.

[0057] The terms “ar” or “aryl” refer to aromatic homocyclic (i.e.,hydrocarbon) mono-, bi- or tricyclic ring-containing groups preferablyhaving 6 to 12 members such as phenyl, naphthyl and biphenyl, as well assuch rings fused to a cycloalkyl, cycloalkenyl, heterocyclo, orheteroaryl ring. Examples include:

[0058] and the like.

[0059] The term “substituted aryl” refers to such aryl groups as definedabove substituted with one or more groups listed in the definition ofT⁴-T⁶, preferably selected from halogen, nitro, alkyl, substitutedalkyl, alkenyl, cyano, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heterocyclo, heteroaryl, oxo, OR₁₁, CO₂R₁₁,C(O)NR₁₂R₁₃, OC(O)R₁₁, OC(O)OR₁₁, OC(O)NR₁₂R₁₃, OCH₂CO₂R₁₁, C(O)R₁₁,NR₁₂R₁₃, NR₁₄C(O)R₁₁, NR₁₄C(O)OR₁₁, NR₁₄C(O)C(O)OR₁₁,NR₁₄C(O)C(O)NR₁₂R₁₃, NR₁₄C(O)C(O)alkyl, NR₁₄C(NCN)OR₁₁, NR₁₄C(O)NR₁₂R₁₃,NR₁₄C(NCN)NR₁₂R₁₃, NR₁₄C(NR₁₅)NR₁₂R₁₃, NR₁₄SO₂NR₁₂R₁₃, NR₁₄SO₂R₁₁, SR₁₁,S(O)R₁₁, SO₂R₁₁, SO₃R₁₁, SO₂NR₁₂R₁₃, NHOR₁₁, NR₁₄NR₁₂R₁₃, N(COR₁₁)OR₁₄,N(CO₂R₁₁)OR₁₄, C(O)NR₁₄(CR₁₆R₁₇)_(r)R₁₁,CO(CR₁₆R₁₇)_(p)O(CR₁₂R₁₃)_(q)CO₂R₁₁, CO(CR₁₆R₁₇)_(r)OR₁₁,CO(CR₁₆R₁₇)_(p)O(CR₁₈R₁₉)_(q)R₁₁, CO(CR₁₆R₁₇)_(r)NR₁₂R₁₃,OC(O)O(CR₁₆R₁₇)_(m)NR₁₂R₁₃, OC(O)N(CR₁₆R₁₇)_(r)R₁₁,O(CR₁₆R₁₇)_(m)NR₁₂R₁₃, NR₁₄C(O)(CR₁₆R₁₇)_(r)R₁₁,NR₁₄C(O)(CR₁₆R₁₇)_(r)OR₁₁, NR₁₄C(═NC)(CR₁₆R₁₇)_(r)R₁₁,NR₁₄CO(CR₁₆R₁₇)_(r)NR₁₂R₁₃, NR₁₄(CR₁₆R₁₇)_(m)OR₁₁,NR₁₄(CR₁₆R₁₇)_(r)CO₂R₁₁, NR₁₄(CR₁₆R₁₇)_(m)NR₁₂R₁₃,NR₁₄(CR₁₆R₁₇)_(n)SO₂(CR₁₈R₁₃)_(q)R₁₁,CONR₁₄(CR₁₆R₁₇)_(n)SO₂(CR₁₈R₁₉)_(q)R₁₁,SO₂NR₁₄(CR₁₆R₁₇)_(n)CO(CR₁₈R₁₉)_(q)R₁₁ and SO₂NR₁₄(CR₁₆R₁₇)_(m)OR₁₁ aswell as pentafluorophenyl.

[0060] The terms “heterocycle”, “heterocyclic”, “heterocyclic group” or“heterocyclo” refer to fully saturated or partially unsaturated cyclicgroups (for example, 3 to 13 member monocyclic, 7 to 17 member bicyclic,or 10 to 20 member tricyclic ring systems, preferably containing a totalof 3 to 10 ring atoms) which have at least one heteroatom in at leastone carbon atom-containing ring. Each ring of the heterocyclic groupcontaining a heteroatom may have 1, 2, 3 or 4 heteroatoms selected fromnitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen andsulfur heteroatoms may optionally be oxidized and the nitrogenheteroatoms may optionally be quaternized. The heterocyclic group may beattached at any heteroatom or carbon atom of the ring or ring system.The rings of multi-ring heterocycles may be either fused, bridged and/orjoined through one or more spiro unions. Exemplary heterocyclic groupsinclude

[0061] and the like.

[0062] The terms “substituted heterocycle” or “substituted heterocyclo”and the like refer to such heterocyclo groups as defined abovesubstituted with one or more groups listed in the definition of T⁴-T⁶,preferably selected from halogen, nitro, alkyl, substituted alkyl,alkenyl, cyano, cycloalkyl, substituted cycloalkyl, aryl, substitutedaryl, heterocyclo, heteroaryl, oxo, OR₁₁, CO₂R₁₁, C(O)NR₁₂R₁₃, OC(O)R₁₁,OC(O)OR₁₁, OC(O)NR₁₂R₁₃, OCH₂CO₂R₁₁, C(O)R₁₁, NR₁₂R₁₃, NR₁₄C(O)R₁₁,NR₁₄C(O)OR₁₁, NR₁₄C(O)C(O)OR₁₁, NR₁₄C(O)C(O)NR₁₂R₁₃, NR₁₄C(O)C(O)alkyl,NR₁₄C(NCN)OR₁₁, NR₁₄C(O)NR₁₂R₁₃, NR₁₄C(NCN)NR₁₂R₁₃, NR₁₄C(NR₁₅)NR₁₂R₁₃,NR₁₄SO₂NR₁₂R₁₃, NR₁₄SO₂R₁₁, SR₁₁, S(O)R₁₁, SO₂R₁₁, SO₃R₁₁, SO₂NR₁₂R₁₃,NHOR₁₁, NR₁₄NR₁₂R₁₃, N(COR₁₁)OR₁₄, N(CO₂R₁₁)OR₁₄,C(O)NR₁₄(CR₁₆R₁₇)_(r)R₁₁, CO(CR₁₆R₁₇)_(p)O(CR₁₈R₁₃)_(q)CO₂R₁₁,CO(CR₁₆R₁₇)_(r)OR₁₁, CO(CR₁₆R₁₇)_(p)O(CR₁₈R₁₉)_(q)R₁₁,CO(CR₁₆R₁₇)_(r)NR₁₂R₁₃, OC(O)O(CR₁₆R₁₇)_(m)NR₁₂R₁₃,OC(O)N(CR₁₆R₁₇)_(r)R₁₁, O(CR₁₆R₁₇)_(m)NR₁₂R₁₃, NR₁₄C(O)(CR₁₆R₁₇)_(r)R₁₁,NR₁₄C(O)(CR₁₆R₁₇)_(r)OR₁₁, NR₁₄C(═NC)(CR₁₆R₁₇)_(r)R₁₁,NR₁₄CO(CR₁₆R₁₇)_(r)NR₁₂R₁₃, NR₁₄(CR₁₆R₁₇)_(m)OR₁₁,NR₁₄(CR₁₆R₁₇)_(r)CO₂R₁₁, NR₁₄(CR₁₆R₁₇)_(m)NR₁₂R₁₃,NR₁₄(CR₁₆R₁₇)_(n)SO₂(CR₁₈R₁₃)_(q)R₁₁,CONR₁₄(CR₁₆R₁₇)_(n)SO₂(CR₁₈R₁₉)_(q)R₁₁,SO₂NR₁₄(CR₁₆R₁₇)_(n)CO(CR₁₈R₁₉)_(q)R₁₁ and SO₂NR₁₄(CR₁₆R₁₇)_(m)OR₁₁.

[0063] The term “heteroaryl” as used herein alone or as part of anothergroup refers to a 5- 6- or 7-membered aromatic rings containing from 1to 4 nitrogen atoms and/or 1 or 2 oxygen or sulfur atoms provided thatthe ring contains at least 1 carbon atom and no more than 4 heteroatoms.The heteroaryl ring is linked through an available carbon or nitrogenatom. Also included within the definition of heteroaryl are such ringsfused to a cycloalkyl, aryl, cycloheteroalkyl, or another heteroarylring. One, two, or three available carbon or nitrogen atoms in theheteroaryl ring can be optionally substituted with substituents listedin the definition of T⁴-T⁶. Also an available nitrogen or sulfur atom inthe heteroaryl ring can be oxidized. Examples of heteroaryl ringsinclude

[0064] and the like.

[0065] The term “substituted heteroaryl” refers to such heteroarylgroups as defined above substituted on any available atom with one ormore groups listed in the definition of T⁴-T⁶, “preferably selectedfrom” refers to such heterocyclo groups as defined above substitutedwith one or more groups listed in the definition of T⁴-T⁶, preferablyselected from halogen, nitro, alkyl, substituted alkyl, alkenyl, cyano,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclo,heteroaryl, oxo, OR₁₁, CO₂R₁₁, C(O)NR₁₂R₁₃, OC(O)R₁₁, OC(O)OR₁₁,OC(O)NR₁₂R₁₃, OCH₂CO₂R₁₁, C(O)R₁₁, NR₁₂R₁₃, NR₁₄C(O)R₁₁, NR₁₄C(O)OR₁₁,NR₁₄C(O)C(O)OR₁₁, NR₁₄C(O)C(O)NR₁₂R₁₃, NR₁₄C(O)C(O)alkyl,NR₁₄C(NCN)OR₁₁, NR₁₄C(O)NR₁₂R₁₃, NR₁₄C(NCN)NR₁₂R₁₃, NR₁₄C(NR₁₅)NR₁₂R₁₃,NR₁₄SO₂NR₁₂R₁₃, NR₁₄SO₂R₁₁, SR₁₁, S(O)R₁₁, SO₂R₁₁, SO₃R₁₁, SO₂NR₁₂R₁₃,NHOR₁₁, NR₁₄NR₁₂R₁₃, N(COR₁₁)OR₁₄, N(CO₂R₁₁)OR₁₄,C(O)NR₁₄(CR₁₆R₁₇)_(r)R₁₁, CO(CR₁₆R₁₇)_(p)O(CR₁₂R₁₃)_(q)CO₂R₁₁,CO(CR₁₆R₇)_(r)OR₁₁, CO(CR₁₆R₁₇)_(p)O(CR₁₈R₁₉)_(q)R₁₁,CO(CR₁₆R₁₇)_(r)NR₁₂R₁₃, OC(O)O(CR₁₆R₁₇)_(m)NR₂R₁₃,OC(O)N(CR₁₆R₁₇)_(r)R₁₁, O(CR₁₆R₁₇)_(m)NR₁₂R₁₃, NR₁₄C(O)(CR₁₆R₁₇)_(r)R₁₁,NR₁₄C(O)(CR₁₆R₁₇)_(r)OR₁₁, NR₁₄C(═NC)(CR₁₆R₁₇)_(r)R₁₁,NR₁₄CO(CR₁₆R₁₇)_(r)NR₁₂R₁₃, NR₁₄(CR₁₆R₁₇)_(m)OR₁₁,NR₁₄(CR₁₆R₁₇)_(r)CO₂R₁₁, NR₁₄(CR₁₆R₁₇)_(m)NR₁₂R₁₃,NR₁₄(CR₁₆R₁₇)_(n)SO₂(CR₁₈R₁₉)_(q)R₁₁,CONR₁₄(CR₁₆R₁₇)_(n)SO₂(CR₁₈R₁₉)_(q)R₁₁,SO₂NR₁₄(CR₁₆R₁₇)_(n)CO(CR₁₈R₁₉)_(q)R₁₁ and SO₂NR₁₄(CR₁₆R₁₇)_(m)OR₁₁.

[0066] In the above definitions, R₁₁, R₁₄, and R₁₅, are independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(O)alkyl,C(O)substituted alkyl, C(O)cycloalkyl, C(O) substituted cycloalkyl,C(O)aryl, C(O)substituted aryl, C(O)Oalkyl, C(O)Osubstituted alkyl,C(O)heterocyclo, C(O)heteroaryl, aryl, substituted aryl, heterocyclo andheteroaryl.

[0067] Also, R₁₂ and R₁₃ are herein defined to be independently selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(O)alkyl,C(O)substituted alkyl, C(O)cycloalkyl, C(O)substituted cycloalkyl,C(O)aryl, C(O)substituted aryl, C(O)Oalkyl, C(O)Osubstituted alkyl,C(O)heterocyclo, C(O)heteroaryl, S(O)₂alkyl, S(O)₂substituted alkyl,S(O)₂cycloalkyl, S(O)₂substituted cycloalkyl, S(O)₂aryl,S(O)₂substituted aryl, S(O)₂heterocyclo, S(O)₂heteroaryl, aryl,substituted aryl, heterocyclo and heteroaryl, or R₁₂ and R₁₃ takentogether with the nitrogen atom to which they are attached complete aheterocyclo or heteroaryl ring.

[0068] R₁₆ and R₁₈ are herein defined to be independently selected fromhydrogen and alkyl or 1 to 4 carbons.

[0069] Finally, in the above definitions, R₁₇ and R₁₉ are independentlyselected from hydrogen, alkyl of 1 to 4 carbons, and substituted alkylor 1 to 4 carbons.

[0070] n is zero or an integer from 1 to 4.

[0071] m is an integer from 2 to 6.

[0072] p is an integer from 1 to 3.

[0073] q is zero or an integer from 1 to 3.

[0074] r is zero or an integer from 1 to 6.

[0075] As used herein, the terms T¹-T¹⁸ are defined below:

[0076] T¹-T³ are independently halo, cyano, nitro, OH, oxo, —OT⁷, —SH,—ST⁷, amino, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,(aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl or(heteroaryl)alkyl.

[0077] T⁴-T⁶ are each independently,

[0078] (1) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,(aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl or(heteroaryl)alkyl, any of which may be optionally independentlysubstituted where valence allows by one or more groups selected fromalkyl, (hydroxy)alkyl, halo, cyano, nitro, OH, oxo, (alkoxy)alkyl,alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,(cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyo)alkyl,heteroaryl, (heteroaryl)alkyl, —OT⁷, —SH, —ST⁷, —C(O)_(t)H, —C(O)_(t)T⁷,—O—C(O)T⁷, —SO₃H, —S(O)_(t)T⁷, S(O)_(t)N(T⁸)T⁷, -T⁹-NT¹¹T¹²,-T⁹-N(T⁸)-T¹⁰-NT¹¹T¹², -T⁹-N(T¹³)-T¹²-T⁷ and -T⁹-N(T¹³)-T¹⁰-H; or

[0079] (2) halo, cyano, nitro, OH, oxo, —OT⁷, —SH, —ST⁷, —OT⁷, —SH,—ST⁷, —C(O)_(t)H, —C(O)_(t)T⁷, —O—C(O)T⁷, —SO₃H, —S(O)_(t)T⁷,S(O)_(t)N(T⁸)T⁷, -T⁹-NT¹¹T¹², -T⁹-N(T⁸)-T¹⁰-NT¹¹T¹², -T⁹-N(T¹³)-T¹²-T⁷or -T⁹-N(T¹³)-T¹⁰-H.

[0080] The variable t is 1 or 2.

[0081] T⁷ is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or(heteroaryl)alkyl.

[0082] T⁹ and T¹⁰ are each independently a single bond,-T¹⁴-S(O)_(t)-T¹⁵-, -T¹⁴-C(O)-T¹⁵-, -T¹⁴-C(S)-T¹⁸-, -T¹⁷-O-T¹⁸-,-T¹⁷-S-T¹⁸-, -T¹⁷-O—C(O)-T¹⁸-, -T¹⁷-C(O)_(t)T¹⁸-, -T¹⁷-C(═NT¹⁶)-T¹⁵- or-T¹⁴-C(O)—C(O)-T¹⁵-.

[0083] The variables T⁸, T¹¹, T¹², T¹³ and T¹⁶ are

[0084] (1) independently hydrogen, alkyl, (hydroxy)alkyl, (alkoxy)alkyl,alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,(cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl,heteroaryl or (heteroaryl)alkyl, any of which may be optionallyindependently substituted where valence permits by one or more groupsselected from alkyl, (hydroxy)alkyl, halo, cyano, nitro, OH, oxo,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyo)alkyl, heteroaryl, (heteroaryl)alkyl, —SH, —ST¹⁹, —C(O)_(t)H,—C(O)_(t)T¹⁹, —O—C(O)T¹⁹ and —S(O)_(t)T¹⁹; or

[0085] (2) independently halo, cyano, nitro, OH, oxo, SH, —ST¹⁹,—C(O)_(t)H, —C(O)_(t)T¹⁹, —O—C(O)T¹⁹ or —S(O)_(t)T¹⁹; or

[0086] (3) T¹¹ and T¹² may together be alkylene or alkenylene,completing a 3- to 8-membered saturated or unsaturated ring togetherwith the atoms to which they are attached, which ring is substitutedwith one or more groups listed in the description of T¹⁷; or

[0087] (4) T¹¹ or T¹², together with T⁸, may be alkylene or alkenylenecompleting a 3- to 8-membered saturated or unsaturated ring togetherwith the nitrogen atoms to which they are attached, which ring issubstituted with one or more groups independently selected from T¹⁷; or

[0088] (5) T¹¹ and T¹² or T⁸ and T¹³ together with the nitrogen atom towhich they are attached may combine to form a group —N═CT¹⁷T¹⁸;

[0089] T¹⁴ and T¹⁵ are each independently a single bond, alkylene,alkenylene or alkynylene;

[0090] T¹⁷ and T¹⁸ are each independently hydrogen, alkyl,(hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocylco)alkyl, heteroaryl or (heteroaryl)alkyl, any ofwhich may be optionally independently substituted where valence permitsby one or more groups selected from alkyl, (hydroxy)alkyl, halo, cyano,nitro, OH, oxo, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyo)alkyl, heteroaryl, (heteroaryl)alkyl, —SH,—ST¹⁹, —C(O)_(t)H, —C(O)_(t)T¹⁹, —O—C(O)T¹⁹ and —S(O)_(t)T¹⁹; and

[0091] T¹⁹ is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or(heteroaryl)alkyl.

[0092] The term “optionally substituted” is intended to be synonymouswith “unsubstituted or substituted”. For example, an optionallysubstituted heterocycle is equivalent to an unsubstituted or substitutedheterocycle.

[0093] “T-cell mediated diseases” refers to any disorder or diseasestate in which modulation of the activity of T-cells is implicated in aprocess which results in either a pathophysiological state or a processwhere the normal function of T-cells is intended to be suppressed fortherapeutic benefit. Examples of T-cell mediated disorders includetransplant rejection, graph verses host disease, and autoimmunedisorders, such as rheumatoid arthritis, multiple sclerosis, juvenilediabetes, asthma, and inflammatory bowel disease, T-cell mediatedhypersensitivity diseases, ischemic or reperfusion injury, and T-cellproliferative disorders. T-cell mediated diseases are included in thedefinition of “leukocyte activation-associated disorders” which isdefined infra.

[0094] The compounds of Formula (I) in accordance with the presentinvention are employed, typically in the form of a pharmaceuticalcomposition including a pharmaceutically acceptable carrier for thetreatment of T-cell mediated disease. The compounds employed for thispurpose are typically administered in an amount from about 0.01 to 100mg/kg/day.

[0095] The pharmaceutical compositions comprising at least one compoundof Formula (I)may be formulated, for example, by employing conventionalsolid or liquid vehicles or diluents, as well as pharmaceuticaladditives of a type appropriate to the mode of desired administration(for example, excipients, binders, preservatives, stabilizers, flavors,etc.) according to techniques such as those well known in the art ofpharmaceutical formulation.

[0096] The compounds of Formula (I) may be administered by any suitablemeans, for example, orally, such as in the form of tablets, capsules,granules or powders; sublingually; buccally; parenterally, such as bysubcutaneous, intravenous, intramuscular, or intrasternal injection orinfusion techniques (e.g., as sterile injectable aqueous or non-aqueoussolutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; or rectally suchas in the form of suppositories; in dosage unit formulations containingnon-toxic, pharmaceutically acceptable vehicles or diluents. The presentcompounds may, for example, be administered in a form suitable forimmediate release or extended release. Immediate release or extendedrelease may be achieved by the use of suitable pharmaceuticalcompositions comprising the present compounds, or, particularly in thecase of extended release, by the use of devices such as subcutaneousimplants or osmotic pumps. The present compounds may also beadministered in the form of liposomes.

[0097] Exemplary compositions for oral administration includesuspensions which may contain, for example, microcrystalline cellulosefor imparting bulk, alginic acid or sodium alginate as a suspendingagent, methylcellulose as a viscosity enhancer, and sweeteners orflavoring agents such as those known in the art; and immediate releasetablets which may contain, for example, microcrystalline cellulose,dicalcium phosphate, starch, magnesium stearate and/or lactose and/orother excipients, binders, extenders, disintegrants, diluents andlubricants such as those known in the art. The present compounds mayalso be delivered through the oral cavity by sublingual and/or buccaladministration. Molded tablets, compressed tablets or freeze-driedtablets are exemplary forms which may be used. Exemplary compositionsinclude those formulating the present compound(s) with fast dissolvingdiluents such as mannitol, lactose, sucrose and/or cyclodextrins. Alsoincluded in such formulations may be high molecular weight excipientssuch as celluloses (avicel) or polyethylene glycols (PEG). Suchformulations may also include an excipient to aid mucosal adhesion suchas hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose(HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydridecopolymer (e.g., Gantrez), and agents to control release such aspolyacrylic copolymer (e.g., Carbopol 934). Lubricants, glidants,flavors, coloring agents and stabilizers may also be added for ease offabrication and use.

[0098] Exemplary compositions for nasal aerosol or inhalationadministration include solutions in saline which may contain, forexample, benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, and/or other solubilizing ordispersing agents such as those known in the art.

[0099] Exemplary compositions for parenteral administration includeinjectable solutions or suspensions which may contain, for example,suitable non-toxic, parenterally acceptable diluents or solvents, suchas mannitol, 1,3-butanediol, water, Ringer's solution, an isotonicsodium chloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

[0100] Exemplary compositions for rectal administration includesuppositories which may contain, for example, a suitable non-irritatingexcipient, such as cocoa butter, synthetic glyceride esters orpolyethylene glycols, which are solid at ordinary temperatures, butliquefy and/or dissolve in the rectal cavity to release the drug.

[0101] Exemplary compositions for topical administration include atopical carrier such as Plastibase (mineral oil gelled withpolyethylene).

[0102] The effective amount of a compound employed in the presentinvention may be determined by one of ordinary skill in the art, andincludes exemplary dosage amounts for an adult human of from about 0.01to 100 mg/kg of body weight of active compound per day, which may beadministered in a single dose or in the form of individual divideddoses, such as from 1 to 4 times per day. It will be understood that thespecific dose level and frequency of dosage for any particular subjectmay be varied and will depend upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of that compound, the species, age, body weight,general health, sex and diet of the subject, the mode and time ofadministration, rate of excretion, drug combination, and severity of theparticular condition. Preferred subjects for treatment include animals,most preferably mammalian species such as humans, and domestic animalssuch as dogs, cats and the like, subject to inflammatory, immunological,or respiratory cell-associated disorders.

[0103] Compounds of Formula (I) include salts, prodrugs and solvates.The term “salt(s)”, as employed herein, denotes acidic and/or basicsalts formed with inorganic and/or organic acids and bases. Zwitterions(internal or inner salts) are included within the term “salt(s)” as usedherein (and may be formed, for example, where the R substituentscomprise an acid moiety such as a carboxyl group). Also included hereinare quaternary ammonium salts such as alkylammonium salts.Pharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salts are preferred, although other salts are useful, forexample, in isolation or purification steps which may be employed duringpreparation. Salts of the compounds of the Formula (I) may be formed,for example, by reacting a compound I with an amount of acid or base,such as an equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

[0104] Exemplary acid addition salts include acetates (such as thoseformed with acetic acid or trihaloacetic acid, for example,trifluoroacetic acid), adipates, alginates, ascorbates, aspartates,benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates,hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates,lactates, maleates, methanesulfonates, 2-naphthalenesulfonates,nicotinates, nitrates, oxalates, pectinates, persulfates,3-phenylpropionates, phosphates, picrates, pivalates, propionates,salicylates, succinates, sulfates (such as those formed with sulfuricacid), sulfonates (such as those mentioned herein), tartrates,thiocyanates, toluenesulfonates, undecanoates, and the like.

[0105] Exemplary basic salts (formed, for example, where the Rsubstituents comprise an acidic moiety such as a carboxyl group) includeammonium salts, alkali metal salts such as sodium, lithium, andpotassium salts, alkaline earth metal salts such as calcium andmagnesium salts, salts with organic bases (for example, organic amines)such as benzathines, dicyclohexylamines, hydrabamines,N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. The basicnitrogen-containing groups may be quaternized with agents such as loweralkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromidesand iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, anddiamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl andstearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyland phenethyl bromides), and others.

[0106] Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound which, upon administration to a subject, undergoes chemicalconversion by metabolic or chemical processes to yield a compound ofFormula (I), or a salt and/or solvate thereof. Solvates of compounds ofFormula (I) are preferably hydrates.

[0107] Various forms of prodrugs are well known in the art. For examplesof such prodrug derivatives, see:

[0108] a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985)and Methods in Enzymology, Vol.42, p. 309-396, edited by K. Widder, etal. (Acamedic Press, 1985);

[0109] b) A Textbook of Drug Design and Development, edited byKrosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and Application ofProdrugs,” by H. Bundgaard, pp. 113-191 (1991); and

[0110] c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992),each of which is incorporated herein by reference.

[0111] Solvates (e.g., hydrates) of the compounds of Formula (I) arealso with the scope of the present invention. Methods of solvation aregenerally known in the art.

[0112] All stereoisomers of the present compounds, such as those whichmay exist due to asymmetric carbons on the R substituents of thecompound of Formula (I), including enantiomeric and diastereomericforms, are within the scope of this invention. Individual stereoisomersof the compounds of the invention may, for example, be substantiallyfree of other isomers, or may be admixed, for example, as racemates orwith all other, or other selected, stereoisomers. The chiral centers ofthe present invention can have an S or R configuration as defined by theIUPAC 1974 Recommendations.

[0113] Preferred Compounds

[0114] Preferred compounds within the scope of the present inventioninclude compounds of Formula (I) (above), or pharmaceutically-acceptablesalts, solvates or prodrugs thereof, in which the substituent L is

[0115] R⁵, R⁶ and R⁷ are

[0116] (1) independently selected from H, alkyl, halo, cyano, nitro, OH,SH, aryl, cycloalkyl, heterocyclo and heteroaryl, any of which isoptionally independently substituted where valence allows with one tothree groups T⁴, T⁵ and/or T⁶; or

[0117] (2) —C(O)N(R⁸)(R⁹), S(O)_(t)N(R⁸)(R⁹), —S(O)_(t)R¹⁰ andC(O)_(t)R¹⁰.

[0118] More preferred compounds of the present invention are selectedfrom Compounds of Formula (II)

[0119] or a pharmaceutically acceptable salt, solvate or prodrugthereof, in which

[0120] R¹, R² R³ and R⁴ are defined as in Formula (I) (above);

[0121] R⁵ is halo, cyano, —C(O)N(R⁸)(R⁹), —S(O)_(t)N(R⁸)(R⁹),—C(O)_(t)R¹⁰ or heteroaryl optionally independently substituted with oneto three groups T⁴, T⁵ and/or T⁶.

[0122] Within the scope of Formula (II), substituents R⁸ and R⁹preferably are

[0123] (1) independently H, alkyl, (cycloalkyl)alkyl or heterocyclo, anyof which is optionally independently substituted where valance allowswith one to three groups independently selected from T⁴, T⁵ and/or T⁶;or

[0124] (2) R⁸ and R⁹ may be taken together with the nitrogen atom towhich they are attached to form a heterocyclo ring optionallyindependently substituted with one to three groups independentlyselected from T⁴, T⁵ and/or T⁶.

[0125] Alternatively, preferred compounds of Formula (I) (above), orpharmaceutically-acceptable salts, solvates or prodrugs thereof, arethose in which

[0126] R² is

[0127] W is O or S (preferably S);

[0128] Y¹ is —NHT¹⁵ or OT¹⁰;

[0129] Y² and Y³ are independently hydrogen, halo, OT⁷, alkyl orhaloalkyl, and

[0130] Y⁴ is optionally substituted heteroaryl, cyano, C(O)_(t)T⁷ orS(O)_(t)NT¹¹T¹².

[0131] Also preferred compounds, are those having Formula (III)

[0132] or pharmaceutically-acceptable salts, solvates or prodrugsthereof, in which

[0133] W is O or S;

[0134] Y¹ is —NHT¹² or OT⁷ (preferably OT⁷, more preferably O C₁₋₄alkyl); and

[0135] Y² is alkyl or haloalkyl (preferably alkyl, more preferably C₁₋₄alkyl).

[0136] Compounds within the scope of Formula (III), or pharmaceuticallyacceptable salts, solvates or prodrugs thereof, are more preferred inwhich

[0137] L is

[0138] and

[0139] R⁵, R⁶ and R⁷ are

[0140] (1) independently selected from H, alkyl, halo, cyano, nitro, OH,SH, aryl, cycloalkyl, heterocyclo and heteroaryl, any of which isoptionally independently substituted where valence allows with one tothree groups T⁴, T⁵ and/or T⁶; or

[0141] (2) —C(O)N(R⁸)(R⁹), S(O)_(t)N(R⁸)(R⁹), —S(O)_(t)R¹⁰ orC(O)_(t)R¹⁰.

[0142] Most preferred compounds within the scope of Formula (III), orpharmaceutically-acceptable salts, solvates or prodrugs thereof, arethose in which:

[0143] L is

[0144] R⁵ is halo, cyano, —C(O)N(R⁸)(R⁹), —S(O)_(t)N(R⁸)(R⁹),—C(O)_(t)R¹⁰ or heteroaryl optionally independently substituted with oneto three groups T⁴, T⁵ and/or T⁶; and

[0145] R⁸ and R⁹ are

[0146] (1) independently H, alkyl, alkenyl, aryl, (aryl)alkyl,heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl,heterocyclo or (heterocyclo)alkyl, any of which is optionallyindependently substituted where valance allows with one to three groupsindependently selected from T⁴, T⁵ and/or T⁶ (preferably H, alkyl,hydroxyalkyl, or heterocyclo, any of which is optionally independentlysubstituted where valance allows with one to three groups selected fromT⁴, T⁵ and/or T⁶); or

[0147] (2) R⁸ and R⁹ may be taken together with the nitrogen atom towhich they are attached to form a heterocyclo or heteroaryl ring(preferably heterocyclo ring), either of which is optionallyindependently substituted where valance allows with one to three groupsindependently selected from T⁴, T⁵ and/or T⁶.

[0148] Preferred compounds within the scope of the present invention arethose having Formula (IV)

[0149] or pharmaceutically-acceptable salts, solvates or prodrugsthereof, in which

[0150] R⁵ is cyano, —C(O)N(R⁸)(R⁹) or heteroaryl;

[0151] R⁸ and R⁹ are

[0152] (1) independently H, alkyl, hydroxyalkyl, or heterocyclo. any ofwhich is optionally independently substituted where valance allows withone to three groups T⁴, T⁵ and/or T⁶; or

[0153] (2) R⁸ and R⁹ may be taken together with the nitrogen atom towhich they are attached to form a heterocyclo which is furtheroptionally independently substituted where valence allows by one tothree groups selected from T⁴, T⁵ and/or T⁶;

[0154] Y¹ is —NHT¹² or OT⁷:

[0155] Y² is alkyl or haloalkyl;

[0156] T⁴-T⁶ are each independently halo, cyano, nitro, OH, oxo, —OT⁷,—SH, —ST⁷, amino, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl,alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,(cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl,heteroaryl or (heteroaryl)alkyl, any of which may be optionallyindependently substituted where valence allows by one or more groupsselected from alkyl, (hydroxy)alkyl, halo, cyano, nitro, OH, oxo,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyo)alkyl, heteroaryl, (heteroaryl)alkyl, —OT⁷, —SH, —ST⁷,—C(O)_(t)H, —C(O)_(t)T⁷, —O—C(O)T⁷, —SO₃H, —S(O)_(t)T⁷, S(O)_(t)N(T⁸)T⁷,-T⁹-NT¹¹T¹², -T⁹-N(T⁸)-T¹⁰-NT¹¹T¹², -T⁹-N(T¹³)-T¹²-T⁷ and-T⁹-N(T¹³)-T¹⁰-H;

[0157] t is 1 or 2;

[0158] T⁷ is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or(heteroaryl)alkyl;

[0159] T⁹ and T¹⁰ are each independently a single bond,-T¹⁴-S(O)_(t)-T¹⁵-, -T¹⁴-C(O)-T¹⁵-, -T¹⁴-C(S)-T¹⁸-, -T¹⁷-O-T¹⁸-,-T¹⁷-S-T¹⁸-, -T¹⁷-O—C(O)-T¹⁸-, -T¹⁷-C(O)_(t)T¹⁸-, -T¹⁷-C(═NT¹⁶)-T¹⁵- or-T¹⁴-C(O)—C(O)-T¹⁴;

[0160] T⁸, T¹¹, T¹², T¹³ and T¹⁶ are

[0161] (1) independently hydrogen, alkyl, (hydroxy)alkyl, (alkoxy)alkyl,alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,(cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl,heteroaryl or (heteroaryl)alkyl, any of which may be optionallyindependently substituted where valence permits by one or more groupsselected from alkyl, (hydroxy)alkyl, halo, cyano, nitro, OH, oxo,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyo)alkyl, heteroaryl, (heteroaryl)alkyl, —SH, —ST⁷, —C(O)_(t)H,—C(O)_(t)T⁷, —O—C(O)T⁷ and —S(O)_(t)T; or

[0162] (2) T¹¹ and T¹² may together be alkylene or alkenylene,completing a 3- to 8-membered saturated or unsaturated ring togetherwith the atoms to which they are attached, which ring is substitutedwith one or more groups listed in the description of T¹⁷; or

[0163] (3) T¹¹ or T¹², together with T⁸, may be alkylene or alkenylenecompleting a 3- to 8-membered saturated or unsaturated ring togetherwith the nitrogen atoms to which they are attached, which ring issubstituted with one or more groups independently selected from T¹⁷; or

[0164] (4) T¹¹ and T¹² or T⁸ and T¹³ together with the nitrogen atom towhich they are attached may combine to form a group —N═CT¹⁷T¹⁸;

[0165] T¹⁴ and T¹⁵ are each independently a single bond, alkylene,alkenylene or alkynylene; and

[0166] T¹⁷ and T¹⁸ are each independently hydrogen, alkyl,(hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocylco)alkyl, heteroaryl or (heteroaryl)alkyl, any ofwhich may be optionally independently substituted where valence permitsby one or more groups selected from alkyl, (hydroxy)alkyl, halo, cyano,nitro, OH, oxo, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyo)alkyl, heteroaryl, or (heteroaryl)alkyl, —SH,—ST¹⁰, —C(O)_(t)H, —C(O)_(t)T¹⁰, —O—C(O)T¹⁰ and —S(O)_(t)T¹⁰.

[0167] More preferable compounds within the scope of Formula (IV), orpharmaceutically-acceptable salts, solvates or prodrugs thereof, arethose in which

[0168] W is S;

[0169] Y¹ is —OC₁₋₄ alkyl; and

[0170] Y² is C₁₋₄ alkyl.

[0171] Even more preferable compounds of Formula (IV) orpharmaceutically-acceptable salts, solvates or prodrugs thereof, arethose in which

[0172] R⁸ and R⁹ are

[0173] (1) independently H, alkyl, hydroxyalkyl or heterocyclo, any ofwhich is optionally independently substituted where valance allows withone to three groups selected from alkyl, cycloalkyl and oxo; or

[0174] (2) R⁸ and R⁹ may be taken together with the nitrogen atom towhich they are attached to form a heterocyclo group optionallysubstituted with oxo.

[0175] Most preferred compounds within the scope of Formula (IV), orpharmaceutically-acceptable salts, solvates or prodrugs thereof, includethose in which R⁵ is selected from:

[0176] Preferred compounds of Formulas (I), (II), (III) and (IV), orpharmaceutically-acceptable salts, solvates or prodrugs thereof, arethose in which R¹ and R⁴ are both H.

[0177] Preferred compounds of Formulas (I), (II), (III) or (IV), orpharmaceutically-acceptable salts, solvates or prodrugs thereof, arethose in which R³ is O.

[0178] Methods of Preparation

[0179] Compounds of Formula I may be prepared by reference to themethods illustrated in the following Schemes A through D. As showntherein the end product is a compound having the same structural formulaas Formula I. It will be understood that any compound of Formula I maybe produced according to Scheme A by the suitable selection ofappropriate substitution. Scheme B shows the preparation of amides fromcompounds of Formula I derived from Scheme A. Scheme C shows thepreparation of tetrazoles from compounds of Formula I derived fromScheme A. Solvents, temperatures, pressures, and other reactionconditions may readily be selected by one of ordinary skill in the art.All documents cited are incorporated herein by reference in theirentirety. Starting materials are commercially available or readilyprepared by one of ordinary skill in the art. Constituents of compoundsare as defined herein or elsewhere in the specification.

[0180] Compounds within the scope of the present invention may beprepared by several methods, including condensation of aryl esters withan appropriately substituted guanidine in the presence of a suitablealkoxide base to provide compounds of Formula 1 as illustrated insynthetic Scheme A. For example, guanidine A1 may be heated with diethylterephthalate in the presence of sodium ethoxide to produce compound A3which is a compound of Formula I.

[0181] L=aryl, cycloalkyl, heterocyclo, or heteroaryl (optionallysubstituted)

[0182] R²=aryl fused with hetero(cyclo or aryl) bonded through aryl, orheteroaryl (all said ring systems optionally substituted)

[0183] Scheme B outlines the conversion of esters of Formula I (depictedin Scheme B where L is phenyl substituted with an ester group; R¹ and R⁴are H; and R³ is O) to amides of Formula I. Hydrolysis of ester B1 underbasic conditions (for instance via lithium hydroxide) affords the acidB2. Coupling of acid B2 under via amide bond coupling techniques(EDC/HOBt) with the appropriately substituted amine, B3, gives thedesired amide, B4.

[0184] The para-substituted acyl guanidines of structures C1, C2 and C3(depicted in Scheme C where L is phenyl substituted with a halogen; R¹and R⁴ are H; and R³ is O) may be prepared as outlined in Scheme A fromcommercially available reagents or by methods which have been reportedin the literature. See e.g., Hallberg, A., et. al., J. Org. Chem., 65,7984 (2000). Selected methods are outlined in Scheme C. Compound C1 maybe prepared via palladium catalyzed cyanation under microwave conditionsto yield intermediate C2. Subsequent conversion to the tetrazole, C3,may be accomplished by microwave heating intermediate C2 with ammoniumchloride and sodium azide.

[0185] Appropriately substituted guanidines referred to in Scheme A, areeither commercially available or may be readily prepared by a number ofmethods known to one skilled in the art of organic chemistry. Forexample, as illustrated in Scheme D, where it is desirable to obtain athienyl group in the R² position, alpha-haloketone D1 may be reactedwith thiobiuret, D2, to provide the guanidine salt D3. D3 is thenliberated from its corresponding salt by treatment with a basic resin,sodium hydroxide, sodium methoxide, or an amine base to provideintermediate D4. D4 can be further elaborated as described in Scheme Ato provide compounds of Formula I.

[0186] Utility

[0187] The compounds of Formula (I), are useful in the treatment(including prevention, partial alleviation or cure) of leukocyteactivation-associated disorders. These disorders include (but are notlimited to) transplant rejection (such as organ transplant, acutetransplant, xenotransplant or heterograft or homograft such as isemployed in burn treatment); protection from ischemic or reperfusioninjury such as ischemic or reperfusion injury incurred during organtransplantation, myocardial infarction, stroke or other causes;transplantation tolerance induction; arthritis (such as rheumatoidarthritis, psoriatic arthritis or osteoarthritis); multiple sclerosis;respiratory and pulmonary diseases including but not limited to asthma,exercise induced asthma, chronic obstructive pulmonary disease (COPD),emphysema, bronchitis, and acute respiratory distress syndrome (ARDS);inflammatory bowel disease, including ulcerative colitis and Crohn'sdisease; lupus (systemic lupus erythematosis); graft vs. host disease;T-cell-mediated hypersensitivity diseases, including contacthypersensitivity, delayed-type hypersensitivity, and gluten-sensitiveenteropathy (Celiac disease); psoriasis; contact dermatitis (includingthat due to poison ivy); Hashimoto's thyroiditis; Sjogren's syndrome;Autoimmune Hyperthyroidism, such as Graves' Disease; Addison's disease(autoimmune disease of the adrenal glands); Autoimmune polyglandulardisease (also known as autoimmune polyglandular syndrome); autoimmunealopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism;Guillain-Barre syndrome; other autoimmune diseases; glomerulonephritis;serum sickness; uticaria; allergic diseases such as respiratoryallergies (e.g., asthma, hayfever, allergic rhinitis) or skin allergies;scleracierma; mycosis fungoides; acute inflammatory and respiratoryresponses (such as acute respiratory distress syndrome andishchemia/reperfusion injury); dermatomyositis; alopecia areata; chronicactinic dermatitis; eczema; Behcet's disease; Pustulosis palmoplanteris;Pyoderma gangrenum; Sezary's syndrome; atopic dermatitis; systemicschlerosis; and morphea.

[0188] The term “leukocyte activation-associated disorder” or “leukocyteactivation-mediated disorder” as used herein includes each of the abovereferenced diseases or disorders. The compounds of the present inventionare useful for treating the aforementioned exemplary disordersirrespective of their etiology.

[0189] The present invention thus provides methods for the treatment ofleukocyte activation-associated disorders (discussed above) comprisingthe step of administering to a subject in need thereof of at least onecompounds of Formula (I). Other therapeutic agents such as thosedescribed below may be employed with the compounds of the presentinvention. In the methods of the present invention, such othertherapeutic agent(s) may be administered prior to, simultaneously withor following the administration of the compound(s) of the presentinvention.

[0190] The methods of treating diseases which would benefit fromadministering compounds of Formula (I) alone or in combination with eachother and/or other suitable therapeutic agents useful in treating suchconditions. These agents include, without limitation: immunosuppressantssuch as cyclosporins (e.g., cyciosporin A), anti-IL-1 agents, such asAnakinra®, the IL-1 receptor antagonist, CTLA4-Ig, antibodies such asanti-ICAM-3, anti-IL-2 receptor (Anti-Tac®), anti-CD45RB, anti-CD2,anti-CD3, anti-CD4. anti-CD80, anti-CD86, monoclonal antibody OKT3,agents blocking the interaction between CD40 and CD154, such asantibodies specific for CD40 and/or CD 154 (i.e., CD40L), fusionproteins constructed from CD40 and CD154 (CD40Ig and CD8-CD154),interferon beta, interferon gamma, methotrexate, FK506 (tacrolimus,Prograf®), rapamycin (sirolimus or Rapamune®)mycophenolate mofetil,leflunomide (Arava®), azathioprine and cyclophosphamide, inhibitors,such as nuclear translocation inhibitors, of NF-kappa B function, suchas deoxyspelgualin (DSG), non-steroidal antiinflammatory drugs (NSAIDs)such as ibuprofen, cyclooxygenase-2 (COX-2) inhibitors such as celecoxib(Celebrex®) and rofecoxib (Vioxx®), or derivatives thereof, steroidssuch as prednisone or dexamethasone, gold compounds TNF-α inhibitorssuch as tenidap, anti-TNF antibodies or soluble TNF receptor such asetanercept (Enbrel®), inhibitors of p-38 kinase such as BIRB-796,RO-3201,195, VX-850, and VX-750, beta-2 agonists such as albuterol,levalbuterol (Xopenex®), and salmeterol (Serevent®), inhibitors ofleukotriene synthesis such as montelukast (Singulair®) and zariflukast(Accolate®), and anticholinergic agents such as ipratropium bromide(Atrovent®), PDE4 inhibitors such as Arofyline, Cilomilast, Roflumilast,C-11294A, CDC-801, BAY-19-8004, Cipamfylline, SCH351591, YM-976,PD-189659, Mesiopram, Pumafentrine, CDC-998, IC-485, and KW-4490, andPDE7 inhibitors such as IC242. See Lee, et al., Cell Signalling, 14,277-284, (2002). Other compounds which may be used in combination withcompounds of Fomula (I) to treat diseases are disclosed in the followingpatent documents: WO 0068230, WO 0129049, WO 0132618, WO 0134601, WO0136425, WO 0174786, WO 0198274, WO 0228847; U.S. Prov. Appl. SerialNos. 60/287,964, and 60/355,141; as well as anti-cytokines such asanti-IL-1 mAb or IL-1 receptor agonist; anti-IL-4 or IL-4 receptorfusion proteins; and PTK inhibitors such as those disclosed in U.S. Pat.Nos. 5,990,109, 6,235,740 and 6,239,133, U.S. Appl. Ser. No. 60/065,042and. Ser. No. 09/173,413, filed Nov. 10, 1997 and Oct. 15, 1998,respectively. All of the foregoing patents and patent applications areincorporated herein by reference in their entirety.

[0191] See also the following documents and references cited therein:Hollenbaugh, D., et al., J. Immunol. Methods, 188(1), 1-7 (1995);Hollenbaugh, D., et al., EMBO J., 11(12),4313-4321 (1992); and Moreland,L. W., et al., New England J. of Medicine, 337(3), 141-147 (1997).

[0192] The above other therapeutic agents, when employed in combinationwith the compounds of the present invention, may be used, for example,in those amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

[0193] Use of the compounds having Formula (I) of the present inventionin treating leukocyte activation-associated disorders is exemplified by,but is not limited to, treating a range of disorders such as: transplant(such as organ transplant, acute transplant, xenotransplant orheterograft or homograft (such as is employed in burn treatment))rejection; protection from ischemic or reperfusion injury such asischemic or reperfusion injury incurred during organ transplantation,myocardial infarction, stroke or other causes; transplantation toleranceinduction; arthritis (such as rheumatoid arthritis, psoriatic arthritisor osteoarthritis); multiple sclerosis; respiratory and pulmonarydiseases including but not limited to asthma, exercise induced asthma,chronic obstructive pulmonary disease (COPD), emphysema, bronchitis, andacute respiratory distress syndrome (ARDS); inflammatory bowel disease,including ulcerative colitis and Crohn's disease; lupus (systemic lupuserythematosis); graft vs. host disease; T-cell mediated hypersensitivitydiseases, including contact hypersensitivity, delayed-typehypersensitivity, and gluten-sensitive enteropathy (Celiac disease);psoriasis; contact dermatitis (including that due to poison ivy);Hashimoto's thyroiditis; Sjogren's syndrome; Autoimmune Hyperthyroidism,such as Graves' Disease; Addison's disease (autoimmune disease of theadrenal glands); Autoimmune polyglandular disease (also known asautoimmune polyglandular syndrome); autoimmune alopecia; perniciousanemia; vitiligo; autoimmune hypopituatarism; Guillain-Barre syndrome;other autoimmune diseases; glomerulonephritis; serum sickness; uticaria;allergic diseases such as respiratory allergies (asthma, hayfever,allergic rhinitis) or skin allergies; scleracierma; mycosis fungoides;acute inflammatory and respiratory responses (such as acute respiratorydistress syndrome and ishchemia/reperfusion injury); dermatomyositis;alopecia areata; chronic actinic dermatitis; eczema; Behcet's disease;Pustulosis palmoplanteris; Pyoderma gangrenum; Sezary's syndrome; atopicdermatitis; systemic schlerosis; and morphea.

[0194] The combined activity of the present compounds towards T-cellsmay be of value in the treatment of any of the aforementioned disorders.

[0195] In a particular embodiment, the compounds of the presentinvention are useful for the treatment of the aforementioned exemplarydisorders irrespective of their etiology, for example, in the treatmentof transplant rejection, rheumatoid arthritis, multiple sclerosis,chronic obstructive pulmonary disease, inflammatory bowel disease,lupus, graft v. host disease, T-cell mediated hypersensitivity disease,psoriasis, Hashimoto's thyroiditis, Guillain-Barre syndrome, cancer,contact dermatitis, allergic disease such as allergic rhinitis, asthma,ischemic or reperfusion injury, respiratory diseases such as asthma,COPD and bronchitis or atopic dermatitis.

[0196] T-cell Proliferation Assay

[0197] Peripheral blood mononuclear cells (PBMC) were isolated fromwhole blood by density gradient centrifugation over Lymphoprep, 1.077.Cells were plated into 96 well U-bottom plates at 2.5×10₅ cells/well in10% FBS RPMI 1640 (Life Technologies/Gibco-BRL) containing 10 ug/mlanti-CD3 (G19-4, Bristol-Myers Squibb P.R.I., Princeton, N.J.) and 1ug/ml anti-CD28 (9.3, Bristol-Myers Squibb P.R.I.) in the presence andabsence of inhibitors. DMSO (used as a solvent for inhibitors) was addedto the medium at 0.1% final concentration. The total volume per well was200 μL. Cells were incubated at 37 C 5% CO2 for 3 days, at which time0.5 μCi of ³H-thymidine was added to each well. Six hours following theaddition of ³H-thmidine, the plates were harvested onto filter plates,30 ul EcoLite scintillant (ICN, Costa Mesa, Calif.) was added per well,and plates read on a Top Count-NXT scintillation counter.

[0198] TNFα Secretion Assay

[0199] The ability of compounds to inhibit the production and secretionof TNFα from leukocytes was performed using either PBMC (obtained asdescribed above) or the THP-1 cell line as a source of monocytes.Compounds were diluted in RPMI 1640 supplemented with 10% FBS and DMSOat a final concentration of 0.2%. Cells (2×10⁵/well in U-bottom 96 wellplates) were pre-incubated with compounds for 30 min at 37 C prior toaddition of lipopolysaccharide (LPS) at a final concentration of 6.25ng/ml in a total volume of 200 μL. After 4 h at 37° C., 50 μL ofsupernatant was carefully aspirated for detection of soluble TNFα.Soluble TNFα was detected by ELISA developed by R&D Systems(Minneapolis, Minn.) according to the manufacturer's instructions.

EXAMPLES

[0200] The following examples illustrate preferred embodiments of thepresent invention and do not limit the scope of the present inventionwhich is defined in the claims. Abbreviations employed in the Examplesare defined below. Compounds of the Examples are identified by theexample and step in which they are prepared (e.g., “A1.1” denotes thetitle compound of step 1 of Example A1), or by the example only wherethe compound is the title compound of the example (for example, “A2”denotes the title compound of Example A2). Abbreviations Ac Acetyl AcOHAcetic acid aq. Aqueous CDI Carbonyldiimidazole Bn Benzyl Bu Butyl Boctert-butoxycarbonyl DMAP Dimethylaminopyridine DMA N,N-DimethylacetamideDMF dimethylformamide DMSO Dimethylsulfoxide EDC1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtOAc Ethylacetate Et Ethyl EtOH Ethanol H Hydrogen h Hours i iso HPLC Highpressure liquid chromatography HOAc Acetic acid Lawesson's Reagent[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4- diphosphetane-2-4-disufide LCliquid chromatography Me Methyl MeOH Methanol min. Minutes M⁺ (M + H)⁺M⁺¹ (M + H)⁺ MS Mass spectrometry n normal Pd/C Palladium on carbon PhPhenyl Pr Propyl Ret Time Retention time rt or RT Room temperature sat.Saturated S-Tol-BINAP(S)-(−)-2,2′-Bis(di-p-tolylphosphino)-1,1′-binapthyl t tert TFATrifluoroacetic acid THE Tetrahydrofuran YMC YMC Inc, Wilmington, NC28403

Example A14-Methyl-2-{N′-[4-(thiomorpholine-4-carbonyl)-benzoyl]-guanidino}-thiazole-5-carboxylicacid ethyl ester

[0201]

A1.1: 2-[(Aminoiminomethyl)amino]-4-methyl-5-thiazolecarboxylic acidethyl ester

[0202]

[0203] A solution of 2-imino-4-thiobiuret (20.0 g, 0.17 mol),2-chloroacetoacetate (28 g, 0.17 mol) in ethanol (500 mL) was heated to100° C. for 4 hours. The reaction mixture was concentrated to halfvolume and poured into 1 liter of 1N NaOH. The white solid whichprecipitated out was collected by filtration and dried under vacuum toyield A1.1 (30.5 g, 79%). ¹H-NMR (DMSO-d₆) δ: 4.22 (2H, q, J=7 Hz ),2.50 (3H, merge with DMSO), 1.26 (3H, t, J=7 Hz ). HPLC: 97.7%, ret.time=1.619 min., LC/MS (M+H)⁺=229.

A1.2:2-[N′-(4-Ethoxycarbonyl-benzoyl)-guanidino]-4-methyl-thiazole-5-carboxlicacid ethyl ester

[0204]

[0205] Sodium (1.1 g, 46.0 mmol) was added in one portion to dry ethanol(50 ml) under a nitrogen atmosphere. After complete consumption of thesodium, A1.1 (3.0 g, 13.0 mmol) was added in one portion and theresulting suspension stirred at room temperature for 30 min. Diethylterephthalate (3.2 g, 14.3 mmol) was then added dropwise over 5 min. andthe reaction mixture was heated to 120 to 130° C. overnight. Thereaction mixture was allowed to cool to room temperature and poured ontowater (50 ml), followed by extraction with ethyl acetate (3×60 ml). Thecombined organics were dried (MgSO₄) and evaporated in vacuo to yieldA1.2 (1.37 g, 26%). ¹H-NMR (DMSO-d₆) δ: 8.10-8.06 (4H, m), 4.36 (2H, q,J=8 Hz ), 4.23 (2H, q, J=8 Hz), 2.56 (3H, s,), 1.35 (3H, t, J=8 Hz),1.30-1.20 (3H, m). HPLC: 95%, ret. time=2.037 min., LC/MS (M+H)⁺=406.17.

A1.3:2-[N′-(4-Carboxy-benzoyl)-guanidino]-4-methyl-thiazole-5-carboxylic acidethyl ester

[0206]

[0207] Lithium hydroxide hydrate (5 mg, 0.12 mmol) was added in oneportion to a solution of A1.2 (40 mg, 0.99 mmol) in 3:1 THF:H₂O (1 ml)and the reaction mixture was allowed to stir at room temperature for 12hours. The reaction mixture was acidified with IN hydrochloric acid (2ml) and the resulting solution extracted with ethyl acetate (3×5 ml).The combined organics were dried (MgSO₄) and evaporated in vacuo. Thecrude acid was purified by column chromatography using 10:1 EtOAc:MeOHas eluent to yield A1.3 (4.4mg, 12%) as a white solid. ¹H-NMR (CD₃OD) δ:8.00-7.89 (4H, m), 4.18 (2H, q, J=7.8 Hz), 2.50 (3H, s,), 1.24 (3H, t,J=7.8 Hz). HPLC: 95%, ret. time=1.797 min., LC/MS (M+H)⁺=377.02.

A1.4:4-Methyl-2-{N′-[4-(thiomorpholine-4-carbonyl)-benzoyl]-guanidino}-thiazole-5-carboxylicacid ethyl ester

[0208] To a solution of A1.3 (70 mg, 0.19 mmol) in DMF (2 mL) was addedthiomorpholine (29 mg, 0.28 mmol), EDC (71 mg, 0.37 mmol), HOBt (50 mg,0.37 mmol) and DIPEA (0.1 ml, 0.56 mmol). The resulting solution wasallowed to stir at room temperature overnight under a nitrogenatmosphere. The reaction mixture was quenched by the addition ofsaturated sodium bicarbonate solution (2 ml) and the aqueous wasextracted with ethyl acetate (3×10 ml). The combined organics were dried(MgSO₄) and evaporated in vacuo. The crude product was purified withprep. HPLC (reverse phase) to yield A1(38 mg, 43%). HPLC: 98%, ret.time=1.797 min., LC/MS (M+H)⁺=462.14.

Example A2-A10

[0209]

[0210] Examples A2-A8 were prepared in a similar manner to that used forExample A1. Example A9 was prepared in a similar manner to A1 except theintermediate A1.1 was reacted with commercially availableethyl-4-bromobenzoate. The cyano- and tetrazole-groups were installed asdescribed in synthetic scheme C. TABLE A1 HPLC Retention MS Ex. Z Name(min) Reported A2

4-Methyl-2-{N′-[4- (morpholine-4-carbonyl)- benzoyl]-guanidino}-thiazole-5-carboxylic acid ethyl ester 1.627 446.17 A3

2-(N′-{4-[(2-Hydroxy-ethyl)- isopropyl-carbamoyl]-benzoyl}-guanidino)-4- methyl-thiazole-5-carboxylic acid ethyl ester1.513 461.16 A4

2-(N′-{4-[Bis-(2-hydroxy- propyl)-carbamoyl]- benzoyl}-guanidino)-4-methyl-thiazole-5-carboxylic acid ethyl ester 1.643 492.13 A5

2-(N′-{4-[(2-Hydroxy-ethyl)- propyl-carbamoyl]-benzoyl}-guanidino)-4-methyl-thiazole-5- carboxylic acid ethyl ester 1.503 461.13A6

4-Methyl-2-{N′-[4-(2-oxo- tetrahydro-thiophen-3- ylcarbamoyl)-benzoyl]-guanidino}-thiazole-5- carboxylic acid ethyl ester 1.687 476.11 A7

2-[N′-(4- Cyclopropylcarbamoyl- benzoyl)-guanidino]-4-methyl-thiazole-5-carboxylic acid ethyl ester 1.823 430.15 A8

2-{N′-[4-(1-Hydroxy-2- methyl-propylcarbamoyl)- benzoyl]-guanidino}-4-methyl-thiazole-5-carboxylic acid ethyl ester 1.793 462.19 A9

2-[N′-(4-Cyano-benzoyl)- guanidino]-4-methyl-thiazole- 5-carboxylic acidethyl ester 1.837 358.01 A10

4-Methyl-2-{N′-[4-(1H- tetrazol-5-yl)-benzoyl]- guanidino}-thiazole-5-carboxylic acid ethyl ester 1.757 401.03

We claim:
 1. A compound of Formula I

enantiomers, diastereomers and pharmaceutically-acceptable salts,solvates or prodrugs thereof, wherein: R¹ and R⁴ are independentlyhydrogen or alkyl optionally independently substituted where valenceallows with one to three groups, T¹, T² and/or T³; R² is

W is O or S. Y¹ is —NHT¹² or OT⁷; Y² and Y³ are independently hydrogen,halo, OT⁷, alkyl, or haloalkyl; Y⁴ is optionally substituted heteroaryl,cyano, C(O)_(t)T⁷ or S(O)_(t)NT¹¹T¹²; and Y⁵ is alkyl, haloalkyl, NHT¹²or OT⁷; R³ is O, S or N; L is aryl, cycloalkyl, heterocyclo orheteroaryl, any of which is independently substituted where valenceallows by one to three groups, R⁵, R⁶ and/or R⁷; R⁵, R⁶ and R⁷ areindependently (1) H, alkyl, halo, cyano, nitro, OH, OR¹⁰, oxo, SH, aryl,cycloalkyl, heterocyclo or heteroaryl, any of which is optionallyindependently substituted where valence allows with one to three groupsT⁴, T⁵ and/or T⁶, provided that when L is aryl or heteroaryl none of R⁵,R⁶ and R⁷ are oxo; or (2) N(R⁸)(R⁹), —C(O)N(R⁸)(R⁹), S(O)_(t)N(R⁸)(R⁹),—S(O)_(t)R¹⁰ or C(O)_(t)R¹⁰; R⁸ and R⁹ are (1) independently H, alkyl,alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl,(cycloalkyl)alkyl, heterocyclo or (heterocyclo)alkyl, any of which isoptionally independently substituted where valance allows with one tothree groups independently selected from T⁴, T⁵ and/or T⁶; or (2) R⁸ andR⁹ may be taken together with the nitrogen atom to which they areattached to form a heterocyclo or heteroaryl ring, either of which isoptionally independently substituted where valance allows with one tothree groups independently selected from T⁴, T⁵ and/or T⁶; R¹⁰ is H,alkyl or substituted alkyl; T¹-T³ are each independently halo, cyano,nitro, OH, oxo, —OT⁷, —SH, —ST⁷, amino, alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocylco)alkyl, heteroaryl or (heteroaryl)alkyl; T⁴-T⁶ are eachindependently (1) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl,alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,(cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl,heteroaryl or (heteroaryl)alkyl, any of which may be optionallyindependently substituted where valence allows by one or more groupsselected from alkyl, (hydroxy)alkyl, halo, cyano, nitro, OH, oxo,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyo)alkyl, heteroaryl, (heteroaryl)alkyl, —OT⁷, —SH, —ST⁷,—C(O)_(t)H, —C(O)_(t)T⁷, —O—C(O)T⁷, —SO₃H, —S(O)_(t)T⁷, S(O)_(t)N(T⁸)T⁷,-T⁹-NT¹¹T¹², -T⁹-N(T⁸)-T¹⁰-NT¹¹T¹²-, -T⁹-N(T¹³)-T¹²-T⁷ and-T⁹-N(T¹³)-T¹⁰-H; or (2) halo, cyano, nitro, OH, oxo, —OT⁷, —SH, —ST⁷,—OT⁷, —SH, —ST⁷, —C(O)_(t)H, —C(O)_(t)T⁷, —O—C(O)T⁷, —SO₃H, —S(O)_(t)T⁷,S(O)_(t)N(T⁸)T⁷, -T⁹-NT¹¹T¹², -T⁹-N(T⁸)-T¹⁰-NT¹¹T¹², -T⁹-N(T¹³)-T¹²-T⁷or -T⁹-N(T¹³)-T¹⁰-H; t is 1 or 2; T⁷ is alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl; T⁹ and T¹⁰ are eachindependently a single bond, -T¹⁴-S(O)_(t)-T¹⁵-, -T¹⁴-C(O)-T¹⁵-,-T¹⁴-C(S)-T¹⁸-, -T¹⁷-O-T¹⁸-, -T¹⁷-S-T¹⁸-, -T¹⁷-O—C(O)-T¹⁸-,-T¹⁷-C(O)_(t)T¹⁸-, -T¹⁷-C(═NT¹⁶)-T¹⁵- or -T¹⁴-C(O)—C(O)-T¹⁵-; T⁸, T¹¹,T¹², T¹³ and T¹⁶ are (1) independently hydrogen, alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl, any of which may beoptionally independently substituted where valence permits by one ormore groups selected from alkyl, (hydroxy)alkyl, halo, cyano, nitro, OH,oxo, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyo)alkyl, heteroaryl, (heteroaryl)alkyl, —SH, —ST¹⁹, —C(O)_(t)H,—C(O)_(t)T¹⁹, —O—C(O)T¹⁹ and —S(O)_(t)T¹⁹; or (2) independently halo,cyano, nitro, OH, oxo, SH, —ST¹⁹, —C(O)_(t)H, —C(O)_(t)T¹⁹, —O—C(O)T¹⁹or —S(O)_(t)T¹⁹; or (3) T¹¹ and T¹² may together be alkylene oralkenylene, completing a 3- to 8-membered saturated or unsaturated ringtogether with the atoms to which they are attached, which ring issubstituted with one or more groups listed in the description of T¹⁷; or(4) T¹¹ or T¹² together with T⁸, may be alkylene or alkenylenecompleting a 3- to 8-membered saturated or unsaturated ring togetherwith the nitrogen atoms to which they are attached, which ring issubstituted with one or more groups independently selected from T¹⁷; or(5) T¹¹ and T¹² or T⁸ and T¹³ together with the nitrogen atom to whichthey are attached may combine to form a group —N═CT¹⁷T¹⁸; T¹⁴ and T¹⁵are each independently a single bond, alkylene, alkenylene oralkynylene; T¹⁷ and T¹⁸ are each independently hydrogen, alkyl,(hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocylco)alkyl, heteroaryl or (heteroaryl)alkyl, any ofwhich may be optionally independently substituted where valence permitsby one or more groups selected from alkyl, (hydroxy)alkyl, halo, cyano,nitro, OH, oxo, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyo)alkyl, heteroaryl, (heteroaryl)alkyl, —SH,—ST¹⁹, —C(O)_(t)H, —C(O)_(t)T¹⁹, —O—C(O)T¹⁹ and —S(O)_(t)T¹⁹; and T¹⁹ isalkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl.
 2. Acompound of claim 1, enantiomers, diastereomers andpharmaceutically-acceptable salts, solvates or prodrugs thereof thereof,wherein: L is

R⁵, R⁶ and R⁷ are (1) independently selected from H, alkyl, halo, cyano,nitro, OH, SH, aryl, cycloalkyl, heterocyclo and heteroaryl, any ofwhich is optionally independently substituted where valence allows withone to three groups T⁴, T⁵ and/or T⁶; or (2) —C(O)N(R⁸)(R⁹),S(O)_(t)N(R⁸)(R⁹), —S(O)_(t)R¹⁰ or C(O)_(t)R¹⁰.
 3. The compound of claim2 having Formula (II)

enantiomers, diastereomers and pharmaceutically-acceptable salts,solvates or prodrugs thereof, wherein R⁵ is heteroaryl optionallyindependently substituted with one to three groups T⁴, T⁵ and/or T⁶,halo, cyano, —C(O)N(R⁸)(R⁹), —S(O)_(t)N(R⁸)(R⁹) or —C(O)_(t)R¹⁰; R⁸ andR⁹ are (1) independently H, alkyl, (cycloalkyl)alkyl or heterocyclo, anyof which is optionally independently substituted where valance allowswith one to three groups independently selected from T⁴, T⁵ and/or T⁶;or (2) R⁸ and R⁹ may be taken together with the nitrogen atom to whichthey are attached to form a heterocyclo ring optionally independentlysubstituted with one to three groups independently selected from T⁴, T⁵and/or T⁶;
 4. A compound of claim 1, enantiomers, diastereomers andpharmaceutically-acceptable salts, solvates or prodrugs thereof,wherein: R² is

W is O or S; Y¹ is —NHT¹⁵ or OT¹⁰; Y² and Y³ are independently hydrogen,halo, OT⁷, alkyl or haloalkyl; and Y⁴ is optionally substitutedheteroaryl, cyano, C(O)_(t)T⁷ or S(O)_(t)NT¹¹T¹².
 5. A compound of claim4, having Formula (III)

enantiomers, diastereomers and pharmaceutically-acceptable salts,solvates or prodrugs thereof, wherein: W is O or S; Y¹ is —NHT¹² orOT¹⁰; and Y² is alkyl or haloalkyl.
 6. A compound of claim 5,enantiomers, diastereomers and pharmaceutically-acceptable salts,solvates or prodrugs thereof, wherein: Y¹ is —OC₁₋₄ alkyl; and Y² isC₁₋₄ alkyl.
 7. A compound of claim 6, enantiomers, diastereomers andpharmaceutically-acceptable salts, solvates or prodrugs thereof,wherein: L is

and R⁵, R⁶ and R⁷ are (1) independently selected from H, alkyl, halo,cyano, nitro, OH, SH, aryl, cycloalkyl, heterocyclo and heteroaryl, anyof which is optionally independently substituted where valence allowswith one to three groups T⁴, T⁵ and/or T⁶; or (2) —C(O)N(R⁸)(R⁹),S(O)_(t)N(R⁸)(R⁹), —S(O)_(t)R¹⁰ or C(O)_(t)R¹⁰.
 8. A compound of claim7, enantiomers, diastereomers and pharmaceutically-acceptable salts,solvates or prodrugs thereof, wherein: R⁵ is halo, cyano,—C(O)N(R⁸)(R⁹), —S(O)_(t)N(R⁸)(R⁹), —C(O)_(t)R¹⁰ or heteroaryloptionally independently substituted with one to three groups T⁴, T⁵and/or T⁶; and R⁸ and R⁹ are (1) independently H, alkyl, alkenyl, aryl,(aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl,(cycloalkyl)alkyl, heterocyclo or (heterocyclo)alkyl, any of which isoptionally independently substituted where valance allows with one tothree groups independently selected from T⁴, T⁵ and/or T⁶; or (2) R⁸ andR⁹ may be taken together with the nitrogen atom to which they areattached to form a heterocyclo or heteroaryl ring, either of which isoptionally independently substituted where valance allows with one tothree groups independently selected from T⁴, T⁵ and/or T⁶. 9 A compoundof claim 8, enantiomers, diastereomers and pharmaceutically-acceptablesalts, solvates or prodrugs thereof, wherein: R⁸ and R⁹ are (1)independently H, alkyl, hydroxyalkyl or heterocyclo, any of which isoptionally independently substituted where valance allows with one tothree groups selected from T⁴, T⁵ and/or T⁶; or (2) R⁸ and R⁹ may betaken together with the nitrogen atom to which they are attached to forma heterocyclo which is further optionally independently substitutedwhere valence allows by one to three groups selected from T⁴, T⁵ and/orT⁶.
 10. A compound of Formula (IV)

enantiomers, diastereomers and pharmaceutically-acceptable salts,solvates or prodrugs thereof wherein: R⁵ is cyano, —C(O)N(R⁸)(R⁹) orheteroaryl; R⁸ and R⁹ are (1) independently H, alkyl, hydroxyalkyl orheterocyclo, any of which is optionally independently substituted wherevalance allows with one to three groups T⁴, T⁵ and/or T⁶; or (2) R⁸ andR⁹ may be taken together with the nitrogen atom to which they areattached to form a heterocyclo which is further optionally independentlysubstituted where valence allows by one to three groups selected fromT⁴, T⁵ and/or T⁶; Y¹ is —NHT¹² or OT⁷; Y² is alkyl or haloalkyl; T⁴-T⁶are each independently (1) alkyl, (hydroxy)alkyl, (alkoxy)alkyl,alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,(cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl,heteroaryl or (heteroaryl)alkyl, any of which may be optionallyindependently substituted where valence allows by one or more groupsselected from alkyl, (hydroxy)alkyl, halo, cyano, nitro, OH, oxo,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyo)alkyl, heteroaryl, (heteroaryl)alkyl, —OT⁷, —SH, —ST⁷,—C(O)_(t)H, —C(O)_(t)T⁷, —O—C(O)T⁷, —SO₃H, —S(O)_(t)T⁷, S(O)_(t)N(T⁸)T⁷,-T⁹-NT¹¹T¹², -T⁹-N(T⁸)-T¹⁰-NT¹¹T¹²,-T⁹-N(T¹³)-T¹²-T⁷ and-T⁹-N(T¹³)-T¹⁰-H; or (2) halo, cyano, nitro, OH, oxo, —OT⁷, —SH, —ST⁷,—OT⁷, —SH, —ST⁷, —C(O)_(t)H, —C(O)_(t)T⁷, —O—C(O)T⁷, —SO₃H, —S(O)_(t)T⁷,S(O)_(t)N(T⁸)T⁷, -T⁹-NT¹¹T¹², -T⁹-N(T⁸)-T¹⁰-NT¹¹T¹², -T⁹-N(T¹³)-T¹²-T⁷or -T⁹-N(T¹³)-T¹⁰-H; t is 1 or 2; T⁷ is alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl; T⁹ and T¹⁰ are eachindependently a single bond, -T¹⁴-S(O)_(t)-T¹⁵-, -T¹⁴-C(O)-T¹⁵-,-T¹⁴-C(S)-T¹⁸-, -T¹⁷-O-T¹⁸-, -T¹⁷-S-T¹⁸-, -T¹⁷-O—C(O)-T¹⁸-,-T¹⁷-C(O)_(t)T¹⁸-, -T¹⁷-C(═NT¹⁶)-T¹⁵- or -T¹⁴-C(O)—C(O)-T¹⁵; T⁸, T¹¹,T¹², T¹³ and T¹⁶ are (1) independently hydrogen, alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl, any of which may beoptionally independently substituted where valence permits by one ormore groups selected from alkyl, (hydroxy)alkyl, halo, cyano, nitro, OH,oxo, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyo)alkyl, heteroaryl, (heteroaryl)alkyl, —SH, —ST¹⁹, —C(O)_(t)H,—C(O)_(t)T¹⁹, —O—C(O)T¹⁹ and —S(O)_(t)T¹⁹; or (2) independently halo,cyano, nitro, OH, oxo, SH, —ST¹⁹, —C(O)_(t)H, —C(O)_(t)T¹⁹, —O—C(O)T¹⁹or —S(O)_(t)T¹⁹; or (3) T¹¹ and T¹² may together be alkylene oralkenylene, completing a 3- to 8-membered saturated or unsaturated ringtogether with the atoms to which they are attached, which ring issubstituted with one or more groups listed in the description of T¹⁷; or(4) T¹¹ or T¹², together with T⁸, may be alkylene or alkenylenecompleting a 3- to 8-membered saturated or unsaturated ring togetherwith the nitrogen atoms to which they are attached, which ring issubstituted with one or more groups independently selected from T¹⁷; or(5) T¹¹ and T¹² or T⁸ and T¹³ together with the nitrogen atom to whichthey are attached may combine to form a group —N═CT¹⁷T¹⁸; T¹⁴ and T¹⁵are each independently a single bond, alkylene, alkenylene oralkynylene; T¹⁷ and T¹⁸ are each independently hydrogen, alkyl,(hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocylco)alkyl, heteroaryl or (heteroaryl)alkyl, any ofwhich may be optionally independently substituted where valence permitsby one or more groups selected from alkyl, (hydroxy)alkyl, halo, cyano,nitro, OH, oxo, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyo)alkyl, heteroaryl, (heteroaryl)alkyl, —SH,—ST¹⁹, —C(O)_(t)H, —C(O)_(t)T¹⁹, —O—C(O)T¹⁹ and —S(O)_(t)T¹⁹; and T¹⁹ isalkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl.
 11. Acompound of claim 10, enantiomers, diastereomers andpharmaceutically-acceptable salts, solvates or prodrugs thereof, whereinW is S; Y¹ is —OC₁₋₄ alkyl: and Y² is C₁₋₄ alkyl.
 12. A compound ofclaim 11, enantiomers, diastereomers and pharmaceutically-acceptablesalts, solvates or prodrugs thereof, wherein: R⁸ and R⁹ are (1)independently H, alkyl, hydroxyalkyl or heterocyclo, any of which isoptionally independently substituted where valance allows with one tothree groups selected from alkyl, cycloalkyl and oxo; or (2) R⁸ and R⁹may be taken together with the nitrogen atom to which they are attachedto form a heterocyclo group optionally substituted with oxo.
 13. Acompound of claim 12, enantiomers, diastereomers andpharmaceutically-acceptable salts, solvates or prodrugs thereof, whereinR⁵ is selected from:


14. A compound of claim 1, enantiomers, diastereomers andpharmaceutically-acceptable salts, solvates or prodrugs thereof, whereinR¹ and R⁴ are both H.
 15. A compound of claim 1, enantiomers,diastereomers and pharmaceutically-acceptable salts, solvates orprodrugs thereof, wherein R³ is O.
 16. A pharmaceutical compositioncomprising at least one compound of claim
 1. 17. A pharmaceuticalcomposition of claim 16 further comprising at least one additionaltherapeutic agent selected from PDE4 inhibitors, consisting of NSAIDs,COX-2 inhibitors, TNF-α inhibitors, beta-2 agonists, anti-cholinergicagents, and steroids.
 18. A method of treating leukocyteactivation-associated disorder which comprises administering aneffective amount of at least one compound of claim 1 to a patient inneed thereof.
 19. A method of claim 18 wherein said leukocyteactivation-associated disorder is selected from transplant rejection,graph verses host disease, rheumatoid arthritis, multiple sclerosis,juvenile diabetes, asthma, inflammatory bowel disease, ischemic orreperfusion injury, cell proliferation and psoriasis.